Acute and chronic pain continue to be the most common complaints that physicians are asked to treat. While acute pain can be managed in most cases, the intense suffering in the cases that are currently difficult to treat demands a constant search for new methods of treatment with fewer side effects and risk of addiction. Chronic pain continues to be very difficult to treat with over $60 billion annually directly spent on treating this disorder. There problems stems from our incomplete understanding of the modulation of acute pain and mechanisms leading to chronic pain. In order for rational development of new therapies for the treatment of acute and chronic pain, it is essential to more thoroughly understand the synaptic, cellular, and molecular mechanisms by which transmission of nociceptive information is modified in the marginal zone (lamina I) and substantia gelatinosa (lamina II) of the spinal cord. This is long-term objective of this proposal. The suggested specific aims for the next 5-year period are: 1. To study how descending inputs modulate synaptic integration of laminae I and II neurons recorded in vivo. 2. To determine the physiological and morphological properties of inhibitory interneurons in laminae I and II recorded in vitro and confirmed in vivo. 3. To analyze the involvement of immediate early genes evoked by noxious stimulation on the long-term modulation of nociceptive behavior. These specific aims will be accomplished by using rats for in vitro and in vivo whole-cell patch clamping techniques. Recordings will be combined with intracellular labeling so that the neuron and its dendritic and axonal arbor can be examined with the light and electron microscope. Putative neurotransmitters will be assessed using immunocytochemical techniques. Antisense oligonucleotide strategies will be combined with behavioral measurement of responses to noxious stimuli in rats to determine the importance of immediate early genes in mediating long-term changes in pain behavior.